Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice

Purpose: To discover drugs lowering PrP in prion-infected cultured neuronal cells that achieve high concentrations in brain to test in mouse models of prion disease and then treat people with these fatal diseases. Methods: We tested 2-AMT analogs for EC and PK after a 40 mg/kg single dose and 40-210 mg/kg/day doses for 3 days. We calculated plasma and brain AUC, ratio of AUC/EC after dosing. We reasoned that compounds with high AUC/EC ratios should be good candidates going forward. Results: We evaluated 27 2-AMTs in single-dose and 10 in 3-day PK studies, of which IND24 and IND81 were selected for testing in mouse models of prion disease. They had high concentrations in brain after oral dosing. Absolute bioavailability ranged from 27-40%. AUC/EC ratios after 3 days were >100 (total) and 48-113 (unbound). Stability in liver microsomes ranged from 30->60 min. Ring hydroxylated metabolites were observed in microsomes. Neither was a substrate for the MDR1 transporter. Conclusions: IND24 and IND81 are active in vitro and show high AUC/EC ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease

Psychiatric and psychosocial challenges in patients undergoing haematopoietic stem cell transplants

Haematological malignancies are often treated with haematopoietic stem cell transplants (HSCT). The disease and its treatment are challenging and life threatening, as they not only affect the recipients, but also their families. This review highlights the available data on the psychological, psychiatric and social impact of these illnesses and their treatment on recipients and families. There are robust data that correlate HSCT with emotional distress, as emotional and physical functioning significantly affect quality of life. Psychiatric co-morbidity including anxiety, depression, adjustment and post-traumatic stress disorder, delirium and cognitive deficits have been reported at different stages in the transplant process. This review will highlight the psychosocial and clinical research findings relevant to HSCT patients and will summarize recommendations for future psychosocial research in this population